Carrier based drug delivery system

Abstract

The present invention relates to a novel drug delivery system of use in the improved delivery of drug therapeutic agents into target cells. The system comprises a drug moiety linked to a carrier moiety wherein the carrier moiety comprises a homeobox peptide or a fragment or derivative thereof.

What is claimed is:  
     
       1. A macromolecule comprising a drug moiety linked to a carrier moiety, wherein
 (a) the drug moiety is not a peptide, an oligonucleotide, cholesterol or biotin and is selected from the group consisting of a cardioprotective drug, an anti-arrhythmic drug, an anti-inflammatory drug, a neuroleptic drug, an anti-convulsant drug, an anxio-lytic drug, an antiviral drug, a diagnostic and a tri-substituted purine;  
 (b) the carrier moiety is a homeobox peptide derived from the helix 3 sequence of the pAntp peptide or fragment thereof; and  
 
       wherein the carrier moiety facilitates the cellular internalization of the drug moiety. 
     
     
       2. The macromolecule of  claim 1 , wherein the drug moiety is a cardioprotective drug. 
     
     
       3. The macromolecule of  claim 1 , wherein the drug moiety is an anti-arrhythmic drug. 
     
     
       4. The macromolecule of  claim 1 , wherein the drug moiety is an anti-inflammatory drug. 
     
     
       5. The macromolecule of  claim 1 , wherein the drug moiety is a neuroleptic drug. 
     
     
       6. The macromolecule of  claim 1 , wherein the drug moiety is an anti-convulsant drug. 
     
     
       7. The macromolecule of  claim 1 , wherein the drug moiety is an anxio-lytic drug. 
     
     
       8. The macromolecule of  claim 1 , wherein the drug moiety is an antiviral drug. 
     
     
       9. The macromolecule of  claim 1 , wherein the drug moiety is a diagnostic. 
     
     
       10. The macromolecule of  claim 1 , wherein the drug moiety is a tri-substituted purine selected from the group consisting of olomoucine, roscovitine and bohemine. 
     
     
       11. The macromolecule of  claim 1 , wherein the carrier moiety comprises a peptide having the amino acid sequence set forth in SEQ ID NO 2. 
     
     
       12. The macromolecule of  claim 1 , wherein the carrier moiety further comprises a cysteine as a terminal residue. 
     
     
       13. The macromolecule of  claim 1 , wherein the carrier moiety comprises a carboxy terminal amino acid residue in which the carboxyl group is converted into a carboxamide group. 
     
     
       14. The macromolecule of  claim 1 , wherein the carrier moiety is comprised of D-amino acids. 
     
     
       15. The macromolecule of  claim 1 , wherein the carrier moiety is in retro-inverso form. 
     
     
       16. A macromolecule comprising a drug moiety linked to a carrier moiety, wherein
 (a) the drug moiety is not a peptide, an oligonucleotide, cholesterol or biotin;  
 (b) the carrier moiety is a homeobox peptide derived from the helix 3 sequence of the pAntp peptide or fragment thereof; and  
 (c) the drug moiety is linked to the carrier moiety by way of a linker moiety;  
 
       wherein the carrier moiety facilitates the cellular internalization of the drug moiety. 
     
     
       17. The macromolecule of  claim 16 , wherein the linker moiety is selected from the group consisting of bi-functional alkyl, aryl, aralkyl and peptidic moieties; multi-functional alkyl, aryl, aralkyl and peptidic moieties; alkyl, aryl and aralkyl aldehydes; alkyl, aryl and aralkyl acids; alkyl, aryl and aralkyl esters; alkyl, aryl and aralkyl anhydrides; sulphydryl groups, and carboxyl groups. 
     
     
       18. The macromolecule of  claim 16 , wherein the linker moiety is selected from the group consisting of maleimido benzoic acid derivatives, maleimido propionic acid derivatives and succinimido derivatives. 
     
     
       19. The macromolecule of  claim 16  wherein the linker moiety is derived from the group consisting of cyanuric bromide, cyanuric chloride, carbonyldiimidazole, succinimidyl esters and sulphonic halides. 
     
     
       20. The macromolecule of  claim 16 , wherein the linker moiety is selected from the group consisting of (methylamino)benzoyl-Cys, succinimidobenzoyl-Cys, succinimidopropionoyl-Cys, β-alanyl-succinyl, acetyl-Cys and (4″-aminoanilino)-succinimidopropionoyl-Cys. 
     
     
       21. The macromolecule of  claim 16 , wherein the linker moiety comprises one to four amino acids selected from the group consisting of cysteine, glycine, glutamic acid and β-alanine. 
     
     
       22. The macromolecule of  claim 16 , wherein the linker moiety comprises a cysteine residue. 
     
     
       23. The macromolecule of  claim 22 , wherein the linker moiety further comprises β-alanine. 
     
     
       24. The macromolecule of  claim 22 , wherein the linker moiety further comprises glycine. 
     
     
       25. The macromolecule of  claim 16 , wherein the linker moiety is a network of lysine residues. 
     
     
       26. The macromolecule of  claim 16 , wherein the carrier moiety bears more than one drug moiety. 
     
     
       27. The macromolecule of  claim 26 , wherein the drug moieties are different. 
     
     
       28. The macromolecule of  claim 26 , wherein each drug moiety is linked to the carrier moiety by way of an identical linker moiety. 
     
     
       29. The macromolecule of  claim 26 , wherein each drug moiety is linked to the carrier moiety by a different linker moiety. 
     
     
       30. A macromolecule comprising a drug moiety covalently bound to a carrier moiety, wherein
 (a) the drug moiety is not a peptide, an oligonucleotide, cholesterol or biotin and is selected from the group consisting of a cardioprotective drug, an anti-arrhythmic drug, an anti-inflammatory drug, a neuroleptic drug, an anti-convulsant drug, an anxio-lytic drug, an antiviral drug, a diagnostic and a tri-substituted purine; and  
 (b) the carrier moiety is a derivative of a homeobox peptide or fragment thereof comprising the amino acid sequence RRMKWKK (SEQ ID No:2), wherein 
 (i) one or two amino acid residues are replaced by a naturally or non-naturally occurring amino acid residue;  
 (ii) there is an insertion of one or more multivalent amino acids;  
 (iii) one or more lysine residues are attached to at least one end;  
 (iv) there is a cysteine as a terminal residue; or  
 (v) any combination of (i)-(iv);  
 
 
       wherein the carrier moiety facilitates the cellular internalization of the drug moiety. 
     
     
       31. A macromolecule comprising a drug moiety linked to a carrier moiety, wherein
 (a) the drug moiety is not a peptide, an oligonucleotide, cholesterol or biotin;  
 (b) the carrier moiety is a derivative of a homeobox peptide or fragment thereof comprising the amino acid sequence RRMKWKK (SEQ ID No:2), wherein 
 (i) one or two amino acid residues are replaced by a naturally or non-naturally occurring amino acid residue;  
 (ii) there is an insertion of one or more multivalent amino acids;  
 (iii) one or more lysine residues are attached to at least one end;  
 (iv) there is a cysteine as a terminal residue; or  
 (v) any combination of (i)-(iv); and  
 
 (c) the drug moiety is linked to the carrier moiety by way of a linker moiety;  
 
       wherein the carrier moiety facilitates the cellular internalization of the drug moiety. 
     
     
       32. The macromolecule of  claim 10 , wherein the tri-substituted purine is roscovitine. 
     
     
       33. The macromolecule of  claim 30 , wherein one or two amino acid residues are replaced by a naturally or non-naturally occurring amino acid residue. 
     
     
       34. The macromolecule of  claim 30 , wherein one or more lysine residues are attached to at least one end. 
     
     
       35. The macromolecule of  claim 30 , wherein one or more lysine residues are attached to at least one end. 
     
     
       36. The macromolecule of  claim 30 , wherein there is a cysteine as a terminal residue. 
     
     
       37. The macromolecule of  claim 31 , wherein one or two amino acid residues are replaced by a naturally or non-naturally occurring amino acid residue. 
     
     
       38. The macromolecule of  claim 31 , wherein there is an insertion of one or more multivalent amino acids. 
     
     
       39. The macromolecule of  claim 31 , wherein one or more lysine residues are attached to at least one end. 
     
     
       40. The macromolecule of  claim 31 , wherein there is a cysteine as a terminal residue.